Objective:

Two functional single nucleotide polymorphisms (SNPs) in the PTPN22 gene (R620W, C1858T, rs24746601; and R263Q, G788A, rs33996649) have been previously associated with autoimmune diseases. The aim of the present study was to investigate the role of the R263Q SNP for the first time and to re-evaluate the role of the R620W PTPN22 polymorphism in the genetic predisposition to systemic sclerosis (SSc) susceptibility and clinical phenotypes.

Methods:

A total of 3422 SSc patients (2020 with limited cutaneous SSc (lcSSc) and 1208 with diffuse cutaneous SSc (dcSSc)) and 3638 healthy controls from an initial case-control set of Spanish Caucasian ancestry, as well as seven independent replication cohorts of Caucasian ancestry (from Belgium, England, Germany, Italy, the Netherlands, USA and Sweden), were included in our study. Genotyping was performed using the TaqMan allelic discrimination assay for both the rs33996649 and the rs2476601 PTPN22 polymorphisms. A meta-analysis was then performed to test the overall effect of these PTPN22 gene polymorphisms in SSc.

Results:

We observed evidence of association of the rs2476601 T allele with SSc susceptibility in the meta-analysis results (P=0.01 pooled, OR=1.15, 95% CI 1.031.28). Moreover, the rs2476601 T allele is significantly associated with anti-centromere (ACA) positive status (P=0.01 pooled, OR=1.22, 95% CI 1.051.42). Although we found that the rs33996649 A allele was significantly associated with SSc in the Spanish population (P=0.02, OR=0.58, 95% CI 0.360.92), this association was not confirmed in the meta-analysis (P=0.36 pooled, OR=0.89, 95% CI 0.721.1).

Conclusion:

Our study suggests that the PTPN22 R620W polymorphism influences SSc genetic susceptibility but that the novel R263Q genetic variant does not. Moreover, our data strengthen the evidence that the R620W mutation is a common risk factor in autoimmune diseases.